Intercepting the Lipid-Induced Integrated Stress Response Reduces Atherosclerosis

Abstract

BackgroundEukaryotic cells can respond to diverse stimuli by converging at serine-51 phosphorylation on eukaryotic initiation factor 2 alpha (eIF2α) and activate the integrated stress response (ISR). This is a key step in translational control and must be tightly regulated; however, persistent eIF2α phosphorylation is observed in mouse and human atheroma.ObjectivesPotent ISR inhibitors that modulate neurodegenerative disorders have been identified. Here, the authors evaluated the potential benefits of intercepting ISR in a chronic metabolic and inflammatory disease, atherosclerosis.MethodsThe authors investigated ISR’s role in lipid-induced inflammasome activation and atherogenesis by taking advantage of 3 different small molecules and the ATP-analog sensitive kinase allele technology to intercept ISR at multiple molecular nodes.ResultsThe results show lipid-activated eIF2α signaling induces a mitochondrial protease, Lon protease 1 (LONP1), that degrades phosphatase and tensin-induced putative kinase 1 and blocks Parkin-mediated mitophagy, resulting in greater mitochondrial oxidative stress, inflammasome activation, and interleukin-1β secretion in macrophages. Furthermore, ISR inhibitors suppress hyperlipidemia-induced inflammasome activation and inflammation, and reduce atherosclerosis.ConclusionsThese results reveal endoplasmic reticulum controls mitochondrial clearance by activating eIF2α-LONP1 signaling, contributing to an amplified oxidative stress response that triggers robust inflammasome activation and interleukin-1β secretion by dietary fats. These findings underscore the intricate exchange of information and coordination of both organelles’ responses to lipids is important for metabolic health. Modulation of ISR to alleviate organelle stress can prevent inflammasome activation by dietary fats and may be a strategy to reduce lipid-induced inflammation and atherosclerosis.

Inflammation in atherosclerotic cardiovascular disease

“…Cholesterol crystals, frequently present in atherosclerotic plaques, can activate the NLRP3 inflammasome pathway to induce secretion of pro-inflammatory and atherogenic cytokines like interleukin 1 beta (IL-1β) and IL-18 18– 22 . Activation of NLRP3 inflammasome requires a priming signal which can be provided by neutrophil-derived extracellular traps and by oxidized lipids followed by the second signal provided by cholesterol crystals 19 .…”

“…Activation of NLRP3 inflammasome requires a priming signal which can be provided by neutrophil-derived extracellular traps and by oxidized lipids followed by the second signal provided by cholesterol crystals 19 . Mitochondrial damage and dysfunction can also play important roles in activating NLRP3 inflammasome 21, 22 .…”

“…Dyslipidemia, especially exposure to saturated fatty acids, induces endoplasmic reticulum stress, mitochondrial oxidative stress, and elF2 alpha phosphorylation which hyperactivates an integrated stress response (ISR), which in turn activates a local and systemic inflammatory response through activation of NLRP3 inflammasome: this process contributes to atherogenesis since inhibition of ISR at different nodes reduces atherosclerosis in hyperlipidemic murine models 22 . Small-molecule ISR inhibitors could emerge as important anti-inflammatory agents for atherosclerosis and other chronic inflammatory conditions 22, 23 .…”

Inflammasome and Mitophagy Connection in Health and Disease

“…In the context of cardiovascular diseases, dysregulation of the cholesterol pathway leads to mitochondrial dysfunction and ROS production, which are related to defective autophagy/mitophagy and further activation of the NLRP3 inflammasome [ 122 ]. Lipid-activated eukaryotic initiation factor 2 α (eIF2α) signaling suppresses Parkin-mediated mitophagy, and reduces mitochondrial damage and inflammasome activation [ 158 ]. Since eIF2α phosphorylation is persistently activated in mouse and human atheroma, blockade of the eIF2α-mediated stress response could prove useful in the treatment of atherosclerosis [ 158 ].…”

“…Lipid-activated eukaryotic initiation factor 2 α (eIF2α) signaling suppresses Parkin-mediated mitophagy, and reduces mitochondrial damage and inflammasome activation [ 158 ]. Since eIF2α phosphorylation is persistently activated in mouse and human atheroma, blockade of the eIF2α-mediated stress response could prove useful in the treatment of atherosclerosis [ 158 ]. In addition, development of nonalcoholic steatohepatitis (NASH) is linked to the impaired mitophagy leading to hepatic NLRP3 inflammasome activation [ 159 ].…”